1-201110216-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000069.3(CACNA1S):c.206C>G(p.Ala69Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 1,614,088 control chromosomes in the GnomAD database, including 2,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A69D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.035 ( 135 hom., cov: 33)

Exomes 𝑓: 0.048 ( 1869 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 7.65

Publications

25 publications found

Variant links:

Genes affected

CACNA1S (HGNC:1397): (calcium voltage-gated channel subunit alpha1 S) This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]

CACNA1S Gene-Disease associations (from GenCC):

congenital myopathy 18
Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hypokalemic periodic paralysis, type 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
malignant hyperthermia, susceptibility to, 5
Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
congenital myopathy
Inheritance: SD, AR, AD Classification: STRONG Submitted by: Illumina, Genomics England PanelApp
hypokalemic periodic paralysis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CACNA1S links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009147704).

BP6

Variant 1-201110216-G-C is Benign according to our data. Variant chr1-201110216-G-C is described in ClinVar as Benign. ClinVar VariationId is 254811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3 link	c.206C>G	p.Ala69Gly	missense_variant	Exon 2 of 44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 link	c.206C>G	p.Ala69Gly	missense_variant	Exon 2 of 43		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 link	c.206C>G	p.Ala69Gly	missense_variant	Exon 2 of 44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.0350

AC:

5326

AN:

152216

Hom.:

134

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0101

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0375

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0391

Gnomad FIN

AF:

0.0463

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0516

Gnomad OTH

AF:

0.0397

GnomAD2 exomes

AF:

0.0362

AC:

9110

AN:

251420

AF XY:

0.0383

show subpopulations

Gnomad AFR exome

AF:

0.00898

Gnomad AMR exome

AF:

0.0200

Gnomad ASJ exome

AF:

0.00973

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.0439

Gnomad NFE exome

AF:

0.0505

Gnomad OTH exome

AF:

0.0349

GnomAD4 exome

AF:

0.0476

AC:

69613

AN:

1461754

Hom.:

1869

Cov.:

AF XY:

0.0475

AC XY:

34522

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.00777

AC:

260

AN:

33480

American (AMR)

AF:

0.0203

AC:

908

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0105

AC:

275

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39698

South Asian (SAS)

AF:

0.0413

AC:

3563

AN:

86252

European-Finnish (FIN)

AF:

0.0447

AC:

2388

AN:

53420

Middle Eastern (MID)

AF:

0.0338

AC:

195

AN:

5768

European-Non Finnish (NFE)

AF:

0.0535

AC:

59443

AN:

1111892

Other (OTH)

AF:

0.0427

AC:

2577

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

3818

7636

11453

15271

19089

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2206

4412

6618

8824

11030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0350

AC:

5326

AN:

152334

Hom.:

135

Cov.:

AF XY:

0.0344

AC XY:

2564

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0100

AC:

417

AN:

41594

American (AMR)

AF:

0.0374

AC:

573

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.0396

AC:

191

AN:

4824

European-Finnish (FIN)

AF:

0.0463

AC:

492

AN:

10622

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0516

AC:

3513

AN:

68020

Other (OTH)

AF:

0.0393

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

256

512

768

1024

1280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0450

Hom.:

123

Bravo

AF:

0.0324

TwinsUK

AF:

0.0556

AC:

206

ALSPAC

AF:

0.0498

AC:

192

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.0541

AC:

465

ExAC

AF:

0.0372

AC:

4510

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0520

EpiControl

AF:

0.0484

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 23, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant hyperthermia, susceptibility to, 5

Benign:3

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypokalemic periodic paralysis, type 1

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital myopathy 18

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Thyrotoxic periodic paralysis, susceptibility to, 1

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;D

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0091

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.5

.;M

PhyloP100

7.7

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.5

N;D

REVEL

Uncertain

0.37

Sift

Benign

0.17

T;T

Sift4G

Benign

0.22

T;T

Polyphen

0.87

.;P

Vest4

0.26

MPC

0.40

ClinPred

0.026

GERP RS

4.9

Varity_R

0.34

gMVP

0.72

Mutation Taster

=69/31

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over